Chiral pyridylphosphines and their application in asymmetric catalytic hydrogenation of 2-arylpropenoic acids

ABSTRACT

Novel, optically active phosphorous compounds of the formula, ##STR1## wherein R 1  represents hydrogen atoms, straight or branched-chain alkyl groups having from 1 to 6 carbon atoms, R 2  represents hydrogen atoms, halogen atoms, lower alkyl groups (1 to 6 carbon atoms), lower alkoxy groups (1 to 6 carbon atoms), hydroxy group, chiral hydroxyalkyl groups, and amino groups (1°, 2°, 3°) vinyl groups or allyl groups and R 3  represents phenyl groups, aryl groups, cyclohexyl groups, substituted and unsubstituted cycloalkyl groups, heteroaromatic rings, are described. The compounds of the formula serve as highly useful ligands in the preparation of ruthenium complexes which are effective catalysts for the asymmetric hydrogenation of 2-arylpropenoic acids leading to high valued 2-arylpropionic acids.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a new class of novel organic atropisomericdiphosphine compounds2,2',6,6'-tetraalkoxy-4,4'-bis(disubstituted-phosphino)-5,5'-disubstituted-3,3'-bipyridineor2,2',6,6'-tetraalkoxy-4,4'-bis(disubstituted-phosphino)-3,3'-bipyridinecompounds {(R)- or (S)-form} and the preparation of these compounds.This invention also relates to the asymmetric catalytic hydrogenation of2-arylpropenoic acids to give the corresponding 2-arylpropionic acids inhigh enantiomeric excess. More particularly, the present inventionrelates to the creation of a class of highly effective chiral catalystswhich can be easily recycled through phase-separation from the products.The improved asymmetric catalytic hydrogenation process of the presentinvention is particularly suitable for use in the synthesis of2-(6'-methoxy-2'-naphthyl)propionic acid (naproxen) and2-(p-isobutylphenyl)propionic acid (S)-ibuprofen!.

2. Prior Art

Atropisomeric diphosphines such as BINAP (J. Am. Chem. Soc. 1980, 102,7932) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl! and its derivativeshave found widespread use in metal-catalyzed asymmetric catalyticreactions. ##STR2##

In particular, BINAP type diphosphines are most useful ligands forenantioselective hydrogenation reactions. Considerable efforts have beenundertaken for the design and synthesis of other atropisomericdiphosphine ligands in biphenyl series, for example BIPHEMP (Eur. Pat.No. 104375, 1983); Helv. Chim. Acta. 1988, 71, 897), BICHEP (Chem. Lett.1989,1849) and MeOBIPHEP (Helv. Chim. Acta. 1991, 74, 370).

The synthesis of BINAP type ligands is difficult. The traditional methodrequires high temperature (˜340° C.) and corrosive conditions to convert2,2'-dihydroxy-1,1'-binaphthene to the key intermediate2,2'-dibromo-1,1'-binaphthene for the synthesis of BINAP. Scientists atMerck (J. Org. Chem. 1994, 59, 7180) and Takasago (Chiral Tech 1996 )reported the synthesis of BINAP by using nickel or palladium catalyzedcoupling reaction of 2,2'-bis(trifluoromethanesulfonyl)oxy!-1,1'-binaphthyl with diphenylphosphine ordiphenylphosphine oxide. This approach requires the expensivetrifluoromethanesulfonic anhydride and several extra steps for thesynthesis of BINAP, MeOBIPHEP, BIPHEMP and BICHEP. The separation of thehomogeneous catalysts from the reaction products is also difficult,making the recycling of the expensive catalysts complicated andconsequently the commerical application of these ligands quiteexpensive.

Naproxen is a nonsteroidal drug with anti-inflammatroy, analgesic andantipyretic activities. It belongs to a group of compounds generallyclassified as arylpropionic acids or arylalkanoic acids. Many syntheticroutes for producing optically pure arypropionic acids have beenproposed. These methods include the resolution of a mixture ofenantiomers by using a resolving agent such as cinchonidine orglucamine. These resolution procedures require numerousrecrystallizations. U.S. Pat. No. 4,542,237 discloses a process forpreparing 2-arylpropionic acids and, in particular, a process forpreparing naproxen, involving a non-catalytic process which is,therefore, not commerically attractive. The asymmetric hydrogenation ofarylpropenoic acid has been previously proposed as a method of producingoptically active 2-arylpropionic acids. For example, Campoli et al.,U.S. Pat. No. 4,239,914 described catalytic asymmetric hydrogenation of2-(6-methoxy-2-naphthyl)acrylic acid utilizing a rhodium catalystcontaining a chiral bidentate phosphine ligand, e.g. DIPAMP, DIOP orPNNP but the enantiomeric excess of the desired product was reported tobe only around 70% or less.

Noyori et al., reported the asymmetric hydrogenation of2-(6'-methoxy-2'-naphthyl)propenoic acid with a catalytic amount of Ru(S)-BINAP!(OAc)₂ at about 13800 KPa H₂ to give naproxen in J. Org. Chem.1987, 52,3174-3176.

Chan et al., also reported the asymmetric catalytic hydrogenation of2-arylpropenic acids with Ru-BINAP type catalysts to produce naproxen inU.S. Pat. No. 4,994,607 and U.S. Pat. No. 5,144,050.

For the economical production of naproxen, S-ibuprofen and other similarproducts, it is highly desirable to invent a new class of catalystswhich are more effective than Ru(BINAP) and are easily separated fromthe reaction products.

SUMMARY OF THE INVENTION

The present invention provides a new class of highly usefulatropisomeric diphosphines, namely (R)- or (S)-form2,2',6,6'-tetraalkoxy-4,4'-bis(disubstituted-phosphino)-5,5'-disubstituted-3,3'-bipyridineor2,2',6,6'-tetraalkoxy-4,4'-bis(disubstituted-phosphino)-3,3'-bipyridineand convenient methods for the synthesis of them and their Ru(II)complexes. This invention also relates to the use of the new Rucatalysts in the asymmetric catalytic hydrogenation of 2-arylpropenoicacids to give the corresponding 2-arylpropionic acids in higherenantiomeric excess than that with the well known Ru(BINAP) catalystsystems under similar reaction conditions. The new catalysts also havethe advantage of being easily separated from the organic product viaphase separation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with a class of novel, opticallyactive phosphorous compounds of the general formula (1) and thesynthetic routes of these ligands as follow. The structure of compoundof formula (1) is shown below: ##STR3## wherein: (a) R¹ is chosen fromthe group comprising hydrogen atoms and straight or branched chain alkylgroups having from 1 to 6 carbon atoms;

(b) R² is chosen from the group comprising hydrogen atom, halogen atoms,lower alkyl groups (1 to 6 carbon atoms), lower alkoxy groups (1 to 6carbon atoms), hydroxy group, chiral alcohol groups, amino groups(1°,2°,3°), vinyl groups and allyl groups; and

(c) R³ is chosen from the group comprising: ##STR4## in which R'represents a straight or branched chain alkyl group having from 1 to 6carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, or anamino group and, where there is more than one group R', each may be thesame or different from the others; or the group P(R³)₂ may form a groupchosen from the following structures: ##STR5## in which R" is a straightor branched chain alkyl group having from 1 to 6 carbon atoms.

A related intermediate, compound (2), is useful for the preparation ofthe key precursor to (1). The structure of (2) is shown below: ##STR6##wherein R¹ and R² are as defined above, and R⁴ represents a lower alkoxygroup, phenoxy group, benzyloxy group or a chlorine or bromine atom.When R⁴ represents halogen atom, compound (2) can react with a compoundof the formula R³ MgX or R³ Li wherein R³ is as defined above and Xrepresents a chlorine, bromine or iodine atom, to give a compound of theformula (3). ##STR7## wherein R¹, R² and R³ are as defined above.Compound (3) can be reduced to compound (1) after separation into theR-form and S-form using chiral HPLC column (for example, Diacel ADcolumn) or via chemical resolution.

The reduction of the R- or S-form compound of formula (3) can be carriedout in a known manner. This can be effected, for example, with a silanesuch as trichlorosilane in an aromatic hydrocarbon solvent such asxylene or toluene in the presence of an auxiliary base such astributylamine or triethylamine. Similar reduction has been used byNoyori et al., (J. Am. Chem. Soc. 1980,102, 7932) for the preparation ofBINAP from BINAPO.

The compounds of formula (2) which are used as a starting material canbe prepared, for example, from a compound of the formula (4) or (5):##STR8## wherein R¹, R², R³ and R⁴ are as defined above, via Ullmanncoupling (Synthesis 1974, 9), to obtain products of formula (2) and (3).This Ullmann coupling reaction can be carried out, for example, byheating a compound of formula (4) or (5) in an inert organic solventsuch as N,N'-dimethylformamide with copper powder activated with iodineto a temperature of about 110° C. to 200° C.

The compounds of general formula (4) and (5), which are used as startingmaterials, can be prepared from a compound of the general formula (6):##STR9## wherein R¹, R² and X are as defined above. Preferably, R² maybe a chlorine, bromine or iodine atom. In a typical preparativeprocedure compound (6) is deprotonated with a base such as lithiumdiisopropylamide at low temperature and the deprotonated intermediate isallowed to react with CIP(R³)₂ or CIP(R⁴)₂ wherein R³ and R⁴ are asdefined above to give a compound of the formula (4) or (5). Compound(6), where the R² represents a chlorine, bromine or iodine atom orhydrogen atom, can be prepared according to a method reported in theliterature (Heterocycles 1988, 27, 11.).

For the purpose of this invention, the catalysts can be prepared by thereaction of diphosphines with Ru(COD)(OAc)₂ (J. Org. Chem.1987,52,3174), Ru(cymene)X₂ !₂ (J. Org. Chem. 1994,59, 3064) orRu(acac)₃ (U.S. Pat. No. 5,144,050, 1992) (in the presence of a reducingagent such as zinc dust in the latter case), wherein COD represents acyclooctadiene group, OAc represents an acetoxy group, X represents ahalogen atom and acac represents an acetylacetonate group in a suitableorganic solvent such as methanol or ethanol, to produce the rutheniumcomplexes.

For the purpose of this invention, the ruthenium complexes can be usedas catalysts in the hydrogenation of 2-arylpropenoic acids. Enantiomericexcesses were determined by chiral HPLC utilizing a SUMICHIRAL OA-2500column. In the following examples, the following abbreviations are used:LDA=lithium diisopropylamide; THF=tetrahydrofuran;DMF=N,N'-dimethylformamide;(PP)=(R)-2,2,6,6'-tetramethoxy-4,4'-diphenylphosphino-3,3'-bipyridine;acac=acetylacetonate; HPLC=high pressure liquid chromatography;sub.=2-(6'-methoxy-2'-naphthyl)propenoic acid.

EXAMPLE 1 Preparation of2,6-dimethoxy-3-bromo-4-(diphenylphosphino)pyridine

To a magnetically stirred solution of 4.0 mL of approximatly 2.0M LDAsolution (in hexane) (7.98 mmol) was added a solution of2,6-dimethoxyl-3-bromopyridine (3.14 g, 6.14 mmol) in 10 mL of THF at-78° C. over a period 20 minutes while the internal temperature was keptbelow -78° C. To the resulting red-brown suspension was added a solutionof chlorodiphenylphosphine (1.20 mL, 6.75 mmol) in the 10 mL of THF at-78° C. The reaction mixture was allowed to warm to ambient temperatureovernight and was poured into 20 mL water. The organic product wasextracted with dichloromethane (3×20 mL). The combined extract was driedwith anhydrous magnesium sulfate and was concentrated in vaccuo to givea crude product which was recrystallized in methanol to give 2.34 g ofpure product (95% theoretical yield).

¹ H-NMR(400 MHz): δ 3.83 (s, 3H, OCH₃), 4.00 (s, 3H, OCH₃), 5.71 (d,J_(PH) =2.4 Hz, 1H, PyH's), 7.38˜7.28 (m, 10H, PhH's).

³¹ P-NMR(161 MHz): δ-4.18 ppm.

¹³ C-NMR(101 MHz): δ 53.61, 54.48, 101.73 (J=27.8 Hz), 106.52 (J=2.1Hz), 128.76 (J=7.6 Hz), 129.38, 134.07, 134.27, 134.33, 134.43, 154.13(J=16.0 Hz), 158.62 (J=5.6 Hz), 161.5.

mass spectrum (high resolution): M.W.=401.0, consistent with C₁₉ H₁₇NPBrO₂, melting point: 149.7°˜150.8° C.

EXAMPLE 2 Preparation of2,6-dimethoxy-3-bromo-4-(diphenylphosphinoyl)pyridine

A round bottom flask with a magnetic stirring bar was charged with2,6-dimethoxy-3-bromo-4-(diphenylphosphino)pyridine (4.96 g) and 50 mLacetone. To this solution was slowly added approximately 35% hydrogenperoxide (33.9 mL). The reaction was monitored by thin-layerchromatography. The product was extracted with 3×20 mL dichloromethane.The combined extract was dried with anhydrous magnesium sulfate and wasconcentrated in vaccuo to give a crude product which was purified bycolumn chromatography (silica gel, CHCl₃ : ethyl acetate=1:1 with 5%NEt₃) to give 5.15 g pure product (96% of theoretical yield).

¹ H-NMR(400 MHz): δ 3.90 (s, 3H, OCH₃), 4.01 (s, 3H, OCH₃), 6.30 (d,J=13.2 Hz, 1H, PyH's), 7.51˜7.47 (m, 4H, PhH's), 7.58˜7.56 (m, 2H,PhH's), 7.74˜7.69 (m, 4H, PhH's).

³¹ P-NMR(161 MHz): δ 30.78 ppm.

¹³ C-NMR(101 MHz): δ 53.94, 54.78, 98.62 (J=4.6 Hz), 108.12 (J=11.1 Hz),128.59 (J=12.7 Hz), 130.01, 131.08, 131.82 (J=11.1 Hz), 132.22 (J=2.0),145.61, 146.58, 159.77 (J=12.2 Hz), 161.65 (J=16.7 Hz).

mass spectrum (low resolution): M.W.=419 (FAB), consistent with C₁₉ H₁₇BrNO₃ P melting point: 149.7°˜150.7° C.

EXAMPLE 3 Preparation of2,2',6,6'-tetramethoxy-4,4'-diphenylphosphinoyl-3,3'-bipyridine

A mixture of 2,6-dimethoxy-3-bromo-4-(diphenylphosphinoyl)pyridine (4.96g, 11.87 mmol), copper powder (2.26 g, 35.60 mmol) and DMF (30 mL) wasstirred at 140° C. for 3 hours. The mixture was evaporated to drynesswith a rotary evaporator at 70° C. The residue was treated for a fewminutes with hot chloroform (30 mL) , the insoluble solid was removed byfiltration and washed with hot chloroform (150 mL), and the combinedfiltrate was dried with anhydrous magnesium sulfate and the solvent wasevaporated. The solid residue was washed with ethyl acetate (30 mL) togive 6.42 g of pure white powder (80% theoretical yield).

¹ H-NMR(400 MHz): δ 3.33 (s, 6H, OCH₃), 3.84 (s, 6H, OCH₃), 6.13 (d,J_(PH) =13.5 Hz, 2H), 7.29˜7.31 (m, 4H, PhH's), 7.44˜7.46 (m, 6H,PhH's), 7.50˜7.57 (m, 6H,PhH's), 7.68˜7.72 (m, 4H, PhH's).

¹³ C-NMR(101 MHz): δ 53.01, 53.39, 104.94 (J=13.1 Hz), 113.13 (J=3.9Hz), 113.20 (J=4.0 Hz), 128.03 (J=2.7 Hz), 128.16 (J=2.9 Hz), 131.35(J=2.7 Hz), 131.39 (J=2.8 Hz), 132.02 (J=9.6 Hz), 132.24 (J=10.3 Hz),133.08 (J=9.2 Hz), 134.17, 143.69, 144.66, 161.00 (J=15.4 Hz), 161.34(J=18.9 Hz).

mass spectrum (low resolution): M.W.=676, consistent with C₃₈ H₃₄ N₂ O₆P₂ melting point: 315.0°˜316.0° C. (decomposed).

EXAMPLE 4 Separation of the enantiomers of2,2',6,6'-tetramethoxy-4,4'-diphenylphosphinoyl-3,3'-bipyridine by HPLC

The enantiomers of2,2',6,6'-tetramethoxy-4,4'-diphenylphosphinoyl-3,3'-bipyridine wereseparated by HPLC with a DAICEL AD column (Sumika Chemical AnalysisService, Ltd.) (25 mm×250 mm). The compounds were eluted with a solventsystem (isopropanol: hexane=20:80) with a flow rate of 3.0 mL perminute. The retention time of the (R)-form isomer was at 12.24 minuteand that of (S)-form isomer was at 25.06 minute.

EXAMPLE 5 Preparation of(R)-2,2',6,6'-tetramethoxy-4,4'-diphenylphosphino-3,3'-bipyridine

A 100 mL, two-necked flask fitted with a magnetic stirring bar and areflux condenser was charged with(R)-2,2',6,6'-tetramethoxy-4,4'-diphenylphosphinoyl-3,3'-bipyridine(1.00 g, 1.50 mmol) and the system was flushed with nitrogen gas. Underthe nitrogen atmosphere, degassed dry toluene (50 mL), triethylamine(2.00 mL, 15.00 mmol) and trichlorosilane (1.50 mL, 15.00 mmol) wereadded to the flask by means of syringes. The mixture was stirred andheated at 120° C. overnight under a nitrogen atmosphere. After thesolution was cooled to room temperature, 30 mL of a 10% aqueous sodiumhydroxide solution was carefully added. The mixture was then stirred at80° C. until the organic and aqueous layers became clear. The organicproduct was extracted with 3×20 mL portions of toluene under a nitrogenatmosphere and the extract was dried over anhydrous magnesium sulfate.The organic layer was concentrated under reduced pressure to give acrude product which was washed with cold degassed methanol to give 0.95g of pure white powdery product (99% theoretical yield).

¹ H-NMR(400 MHz): δ 3.30 (s, 6H, OCH₃), 3.81 (s, 6H, OCH₃), 6.02 (d,J_(PH) =1.2 Hz, 2H, PyH's), 7.18 (d, J_(HH) =3.3 Hz, 4H, PhH's),7.31˜7.26 (m, 16H, PhH's).

¹³ C-NMR(101 MHz): δ 52.92, 53.28, 105.05, 114.42, 114.60, 114.78,128.03, 128.06, 128.10, 128.22, 128.35, 128.38, 128.43, 128.64, 133.40,133.50, 133.60, 134.36, 134.47, 134.58, 135.13, 135.18, 135.23,136.71.136.78, 136.85, 154.02, 154.08, 154.14, 160.61, 160.67, 160.73,162.28

³¹ P-NMR(161 MHz): δ-12.18 ppm.

mass spectrum (high resolution): M.W.=644.2, consistent with C₃₈ H₃₄ N₂O₄ P₂ α!^(D) =+36.4° (C=1.1 in CH₂ Cl₂).

EXAMPLE 6 Preparation of Ru (cymene)(PP)Cl!Cl

To a mixture of(R)-2,2',6,6'-tetramethoxy-4,4'-diphenylphosphino-3,3'-bipyridine (46.5mg, 0.072 mmol) and Ru(cymene)Cl₂ !₂ (21.5 mg, 0.035 mmol) in a Schlenktube was added ethanol (5 mL) and dichloromethane (1 mL). The mixturewas stirred at 50° C. for one hour and then was filtered through acelite pad. The resulting orange yellow solution was concentrated underreduced pressure to afford 32.4 mg catalyst (97% theoretical yield).

³¹ P-NMR(161 MHz): δ 27.35 (d, J=61.7 Hz), 41.6 (d, J=61.3 Hz).

EXAMPLE 7 Preparation of Ru(acac)₂ (PP)

A 50 mL two-necked flask was charged with Ru(acac)₃ (125 mg, 0.31 mmol),(R)-2,2',6,6'-tetramethoxy-4,4'-diphenylphosphino-3,3'-bipyridine (200mg, 0.31 mmol), zinc dust (201 mg) and degassed ethanol (5 mL) under anatmosphere of nitrogen gas. The mixture was heated to reflux overnightand followed by filtration through a celite pad. The resulting brownishyellow solution was concentrated under reduced pressure to give 284.07mg of brownish yellow solid (97% theoretical yield).

³¹ P-NMR(161 MHz); δ 56.64, 57.05 ppm.

EXAMPLE 8

This example illustrates the effect of solvent on the rate andenantioselectivity of the Ru(cymene)(PP)Cl!Cl catalyzed asymmetrichydrogenation leading to naproxen.

A glass-lined stainless steel autoclave reactor was charged with 5.00 mgof 2-(6'-methoxy-2'-naphthyl)propenoic acid, 0.10 mg Ru(cymene)(PP)Cl!Cland 2.50 mL of solvent. The solution was stirred well with a magneticstirrer for 6˜18 hours. Typical results are summarized in Table 1.

                  TABLE 1    ______________________________________    The Effect of Solvent on the Hydrogenation of 2-(6'-    methoxy-2'-naphthyl)propenoic acid                      reaction    entry.sup.(a)           solvent    time (hrs)                                conv.(%).sup.(b)                                         e.e.(%).sup.(b)    ______________________________________    1      acetone    15        0        --    2      acetonitrile                      18        0        --    3      chloroform 15        1.4      --    4      diethyl ether                      18        100      69.5    5      THF        15        91.6     70.7    6      i-PrOH     18        80.8     75.0    7      EtOH       15        53.6     77.6    8      CH.sub.3 OH                       6        100      87.0    ______________________________________     .sup.(a) H.sub.2 pressure = 6896 KPa; substrate/catalyst = 200 (molar     ratio); concentration of substrate 2.0 mg/mL, ambient temperature.     .sup.(b) The conversion and enantiomeric excess were determinated by HPLC     analysis with a SUMICHIRAL OA2500 column (Sumika Chemical Analytical     Service, Ltd.).

EXAMPLE 9

This example illustrates the effect of reaction pressure on theenantiomeric excess of desired product (naproxen) by using Ru(acac)₂(PP) as catalyst.

A glass-lined stainless steel reactor was charged with 5.00 mg of2-(6'methoxy-2'-naphthyl)propenoic acid, 0.10 mg Ru(acac)₂ (PP) and 2.50mL of methanol. The solution was stirred well with a magnetic stirrer ata chosen hydrogen pressure for 10 hours. Typical results are summarizedin Table 2. It was noted that higher hydrogen pressure gave higherenantiomeric excess for the naproxen product.

                  TABLE 2    ______________________________________    The Effect of Hydrogen Pressure on    the Hydrogenation of 2-(6'-methoxy-2'-    naphthyl)propenoic acid    entry.sup.(a)  P(KPa)  e.e.(%).sup.(b)    ______________________________________    1              3448    86.8    2              5172    88.7    3              5896    91.5    4              8276    91.9    ______________________________________     .sup.(a) substrate catalyst = 200 (molar ratio); concentration of     substract = 2.0 mg/mL; ambient temperature; complete conversion (100%) in     all cases.     .sup.(b) The enantiomeric excess was determinated by HPLC analysis with a     SUMICHIRAL OA2500 column (Sumika Chemical Analytical Service, Ltd.).

EXAMPLE 10

This example illustrates the effect of the addition of an acid to thecatalyst system on the enantiomeric excess in the hydrogenation of2-(6'-methoxy-2'napthyl)propenoic acid.

A glass-lined stainless steel reactor was charged with 5.00 mg of2-(6'-methoxy-2'-naphthyl)propenoic acid, 0.10 mg Ru(acac)₂ (PP), 2.50mL of methanol and a certain amount of phosphoric acid. The solution wasstirred well with a magnetic stirrer at ambient temperature. Typicalresults are shown in Table 3.

                  TABLE 3    ______________________________________    The Effect of phosphoric acid on the    Hydrogenation of 2-(6'-methoxy-    2'-naphthyl)propenoic acid                  H.sub.3 PO.sub.4 /sub.    entry.sup.(a) (mole %)  e.e.(%).sup.(b)    ______________________________________    1             0         91.5    2             0.2       91.6    3             0.4       92.7    4             0.6       93.6    5             0.8       93.0    6             1.0       92.7    ______________________________________     .sup.(a) H.sub.2 pressure = 6896 KPa; substrate/catalyst = 200 (molar     ratio); concentration of substract = 2.0 mg/mL; 13 hours; ambient     temperature; 2.5 mL of MeOH; complete conversion (100%) in all case.     .sup.(b) The enantiomeric excess was determinated by HPLC analysis with a     SUMICHIRAL OA2500 column (Sumika Chemical Analytical Service, Ltd.).

It was found that a suitable amount of phosphoric acid (0.5˜0.6equivalent to 2-(6'-methoxy-2'-naphthyl)propenoic acid) increased theenantiomeric excess of product and made the system commerically moreattractive. On a side-by-side comparison study, the hydrogenation of2-(6'-methoxy-2'-naphthyl)propenoic acid with the well knownRu(BINAP)(OAc)₂ catalyst under 6896 KPa hydrogen and at ambienttemperature gave only 89% e.e. The results in this example clearlydemonstrated the advantage of this new class of chiral ligands andcatalysts.

EXAMPLE 11

This example illustrates the effect of reaction temperature on theenantiomeric excess of the desired product (naproxen) by using Ru(acac)₂(PP) as catalyst.

A glass-lined stainless steel reactor was charged with 0.02 g of2-(6'-methoxy-2'-naphthyl)propenoic acid, 0.10 mg Ru(acac)₂ (PP) and2.00 mL of methanol. The solution was pressurized with 6896 KPa H₂ andwas stirred well with a magnetic stirrer at a fixed temperature. Typicalresults are summarized in Table 4. It was noted that lower reactiontemperature gave higher enantiomeric excess for the naproxen product.

                  TABLE 4    ______________________________________    The Effect of Reaction Temperature on the    Hydrogenation of 2-(6'-methoxy-2'-    naphthyl)propenoic acid            H.sub.3 PO.sub.4 /sub.    entry.sup.(a)            (mol %)        T (°C.)                                   e.e. (%).sup.(b)    ______________________________________    1       0              25      91.5    2       0              0       95.3    3       0.6            25      93.6    4       0.6            0       96.2    5       0.5            0       95.5    ______________________________________     .sup.(a) H.sub.2 pressure = 6896 KPa; substrate/catalyst 800 (molar     ratio); concentration of substract = 10.0 mg/mL; 18 hours; 2.0 mL of MeOH     complete conversion (100%) in all cases.     .sup.(b) The enantiomeac excess was determinated by HPLC analysis with a     SUMICHIRAL OA2500 column (Sumika Chemical Analytical Service, Ltd.).

EXAMPLE 12 This example illustrates the convenient recycling of the newcatalyst.

A stainless steel reactor was charged with a pre-mixed solution ofRu(acac)₂ (PP)! (6.46×10⁻² mg, 6.85×10⁻⁵ mmol),2-(6'-methoxy-2'-naphthyl)propenoic acid (12.5 mg, 5.48×10⁻² mmol) andMeOH (1.00 mL). (The solution had been exposed to visible light for 24hours before use.) The autoclave was pressurized with 6896 KPa hydrogenand stirred well with a magnetic stirrer at ambient temperature. After30 minutes of reaction, the gas was vented and the solution wasconcentrated under reduced pressure. The enantiomeric excess andconversion yield of product were determined by HPLC analysis with aSUMICHIRAL OA-2500 column (Sumika Chemical Analytical Service, Ltd.)(e.e=91.6%, conversion yield=100%).

The solution containing the product was mixed with ethyl acetate (3.00mL) and was extracted with 9N sulfuric acid solution (0.50 mL×2). Theaqueous layer was poured into a Schlenk flask. Saturated aqueous sodiumcarbonate solution was added to neutralize the acidic solution to pH=7under rapid stirring at 5° C. The solution was successively extractedwith toluene (3.00 mL×2) and the toluene layer was separated and theruthenium content was measured by atomic absorption spectrometry (96% ofthe starting ruthenium was found to be in this recycled solution)toluene solution was then concentrated to dryness under reducedpressure. The residue was dissolved in methanol (1 mL) and filteredthrough a celite-pad into a Schlenk flask. The recycled catalystsolution was used to repeated the hydrogenation of2-(6'-methoxy-2'-naphthyl)propenoic acid (12.5 mg, 5.48×10⁻² mmol)following the previous procedure. The catalyst activity andenantioselectivity was found to be similar to those of the freshlyprepared catalyst. The enantiomeric excess and conversion yield ofnaproxen was determinated again by HPLC analysis with a SUMICHIRALOA-2500 column (e.e=91.6%, conversion yield=100%).

We claim:
 1. A chiral pyridylphosphine having the following formula (1):##STR10## wherein: (a) R¹ represents a hydrogen atom or a straight orbranched-chain alkyl group having from 1 to 6 carbon atoms;(b) R² ischosen from the following group:hydrogen atoms; halogen atoms; straightor branched-chain alkyl groups having 1 to 6 carbon atoms; straight orbranched-chain alkoxy groups having from 1 to 6 carbon atoms; hydroxygroup; straight or branched-chain chiral hydroxyalkyl groups having from1 to 6 carbon atoms; amino groups; mono- and di-alkylamino groups inwhich the alkyl group has from 1 to 6 carbon atoms; vinyl groups; andallyl groups; and (c) R³ is chosen from the following groups: ##STR11##in which R' represents a straight or branched chain alkyl group havingfrom 1 to 6 carbon atoms, a straight or branched-chain alkoxy grouphaving from 1 to 6 carbon atoms or an amino group and, where there ismore than one group R', each R' may be the same or different from theothers; orthe group P(R³)₂ may form a group chosen from the following:##STR12## in which R" is a straight or branched-chain alkyl group havingfrom 1 to 6 carbon atoms.
 2. The chiral pyridylphosphine of claim 1wherein formula (1) comprises2,2',6,6'-tetramethoxy-4,4'-diphenylphosphino-3,3-bipyridine.
 3. Thechiral pyridylphosphine of claim 2, wherein the chiral pyridylphosphineis in (S) form.
 4. The chiral pyridylphosphine of claim 2, wherein thechiral pyridylphosphine is in (R) form.
 5. A process for the preparationof the formula (1) as defined in claim 1, comprising reducing a compoundof formula (3), as defined below, using a silane compound: ##STR13##wherein R¹ , R² and R³ are previously defined.
 6. The process accordingto claim 5, wherein the silane is trichlorosilane and reducing iscarried out in an aromatic hydrocarbon solvent in the presence of anorganic base.